Computational Modelling And Mechanism Of Cardiac Biological Pacemaker

Since the first electronic pacemaker was applied in clinic 60 years ago,it has saved a million lives all over the world.However,there are still several shortcomings.For instance,electronic pacemakers are sensitive to electromagnetic interference and cannot response to emotion.As a result,biological pacemaker（BP）therapy was proposed as a new treatment for pacing dysfunction.The ionic channel protein of unexcitable cardiac myocytes（CMs）is re-edited by gene engineering,in which ionic channel currents are changed,so that cells are transformed into pacemaker cells（PCs）.This kind of artificial PCs is believed to replace electrode and drive heartbeat.Whereas,several questions about BP therapy still need to be solved,such as how ionic currents affect BP construction,if cell coupling and spatial distribution have an impact on BP’s capacity.These problems are difficult to be quantificationally studied in biological experiments.Therefore,in this paper,a BP treatment is designed using cardiac electrophysiology model method,in which the key factors influencing the construction of BP are explored.Main research contents of this dissertation are as follows.（1）Biological experiments indicated that funny current（I_f）can induce automaticity in ventricular myocytes（VMs）,but can lead to abnormal pacemaking behaviors,whose underlying mechanisms are not clear.Therefore,species-dependent I_f model was built and incorporated into a human VMs model to study the effect of I_fon the automaticity of VM model.In this model,the reasons why I_f promoted pacemaking behavior and how I_f cause abnormal pacing behaviors were illustrated.Based on the mechanisms,an optimized model was presented.Finally,according to the pacemaking safe mechanism of sinoatrial node,the effects of extra T-type calcium current(I_{Ca T})on the pacemaking behavior of I_f-induced pacemaker were explained.（2）Biological experiments and our previous simulation presented that the stability of BP induced by single ionic channel cannot be satisfied with physiological needs.As a result,a BP model was constructed based on the reciprocal interaction between multiple ion channels by reconstructing inward rectifying potassium current(I_K1)and I_f.Action potential recognition algorithm and automatic classification algorithm were designed to analyze simulation results,by which five different membrane potential states were classified and deeply investigated.Then,the differences and correlations of I_K1 and I_f current density when inducing automaticity were further explained.Finally,a stable BP cell model that can satisfy human heartbeat cycle length was constructed.（3）The drive efficiency of BP in the previous biological and simulation research was much less than the pacemaking ability of sinoatrial node.In this study,weak and rectifying coupling model were constructed and integrated into BP tissue model to promote its drive capacity.First,the protective effect of weak coupling between PCs on its automaticity was studied.Then,rectifying model between PC and VM was used to suppress the load effect of VMs on PCs.Simulation results showed that the interaction of weak and rectifying coupling can release the maximum drive capacity of BP.（4）The spatial structure is crucial to the propagation of cardiac electrical waves,but what kind of spatial distribution（location）of BP has best drive capacity is not clear.In this study,the effect of BP location and cell coupling mode on pacemaking drive capacity was investigated.Three typical pacemaker-ventricular tissues were designed and their electrical signals distribution was calculated under normal or weak-rectifying cell coupling.Results showed that isolated pacemaker with weak-rectifying cell coupling presented the best performance.Finally,the pacemaker implantation scheme for a 2D human heart slice was designed and the effect of BP location on synchronous pacing was investigated.This method can be used in designing personalized BP therapy.This study elucidated the underlying mechanisms and possible risks of PCs transformed from unexcitable cells and proposed the possibility of improving the drive capacity of BP by changing the cell coupling mode and spatial structure,which provides new insights and future research for the clinical research of BP.